To evaluate p-cell function in patients with pancreatic cancer, the glucagon stimulation test was performed in seven patients with pancreatic adenocarcinoma, seven patients with type I diabetes mellitus, seven patients with type I1 diabetes mellitus, and in seven healthy controls. C-peptide serum levels were determined before and after a 1-mg i.v. glucagon injection. Basal C-peptide values were normal or slightly increased in pancreatic cancer and type I1 diabetic patients and low in type I diabetic patients. Following glucagon stimulation, no significant increase was observed in C-peptide values of type I diabetics and pancreatic cancer patients, whereas significant increases occurred in controls and type I1 diabetics. It is concluded that the altered p-cell function found in pancreatic cancer patients may lead to hyperglycemia, which is frequently associated with this tumor type.
We evaluated levels of insulin-like growth factor-I and interleukin-1 alpha and beta in patients with pancreatic cancer; the role of these substances in tumor spread and in hyperglycemia was also investigated. Thirty pancreatic cancer patients (21 with hyperglycemia) were compared with others with diseases causing hyperglycemia [liver cirrhosis (14 cases, 12 with hyperglycemia), chronic pancreatitis (20 cases, 12 with hyperglycemia), type I diabetes mellitus (13 cases, all hyperglycemic)]. Insulin-like growth factor-I was significantly reduced in patients with liver cirrhosis, probably due to a reduced hepatic capacity for synthesis. It was increased in 6 of 30 pancreatic cancer patients; in these subjects it was correlated with alanine aminotransferase and C-peptide, but not with tumor diameter or the presence of metastases. Interleukin-1 alpha and beta were both elevated in pancreatic cancer patients. The former was high, while the latter was low when liver metastases were present. Neither was related to glucose or C-peptide levels. In summary, insulin-like growth factor-I levels are increased in some pancreatic cancer patients but this does not seem to favor tumor spread; however IGF-I could be involved influencing glucose homeostasis. Interleukin-1 alpha increased, while interleukin-1 beta decreased in pancreatic cancer patients with metastases, suggesting a different involvement of these two substances in pancreatic cancer spread.
Renal function may be compromised by extrahepatic cholestasis. In this context, the nephrotoxic role of bile salts is well known. Recently, however, it has been claimed that other factors, such as lipid peroxides, are involved. We therefore created bile duct ligation in 40 Sprague-Dawley rats. During the follow-up (from 1 to 28 days), significant variations were found in liver histological parameters, but not in renal morphology. Fourteen days after ligation, significant increases were found in serum and urinary thiobarbituric-acid-reactive species and phospholipase A2 (indirect indices of lipid peroxidation), whereas 8-10 days after ligation, a significant decrease was observed in erythrocytic and hepatic GSH levels. The variations in urinary thiobarbituric-acid-reactive species and in phospholipase A2 were not correlated with concomitant variations in the sera. Urinary lipid peroxides were directly correlated with the degree of liver morphological alterations and inversely with circulating GSH. Urinary outputs of lipid peroxides, phospholipase A2 and N-acetyl-glucosaminidase were correlated with each other. These results suggest that there is an imbalance in the oxidative-antioxidant hepatic system in experimental extrahepatic cholestasis. The reduced bioavailability of blood GSH may alter the oxidative equilibrium in other organs, such as the kidney, triggering and favoring the lipoperoxidative cascade.
In this study we assessed whether conditioned media from a human pancreatic cancer cell line (MIA PaCa 2) can interfere with some intracellular pathways involved in glucose metabolism in isolated rat hepatocytes. The hepatocytes. isolated from Male Wistar rats, were incubated with MIA PaCa 2-conditioned or nonconditioned media. Conditioned and nonconditioned hepatocytes were run for 120 min in the presence or absence of insulin (100 m M ) and were sampled at fixed time intervals. Supernatant glucose levels decreased to a similar extent over time in both conditioned and nonconditioned hepatocytes, while lactate levels significantlly increased in nonconditioned hepatocytes with respect to conditioned hepatocytes. A pyruvate kinase activity increase was observed only in nonconditioned hepatocytcs and was biphasic in nature, since this increased activity was dctccted both after a few and after 30 min following insulin stimulation. The cyclic A M P level increase was significantly higher in conditioned than in nonconditioned hepatocytes. It appears that MIA PaCa 2 cells produce a factor(s) that may interfere with one of the insulin-mediated intracellular pathways of glucose metabolism, namely, glycolysis. This detrimental effect on glycolysis is supported by the blunted rise in lactate concentration in the medium after the glucose challenge. This substance(s) probably transfers its signal inside the target cells, activating the adenylate cyclase pathway. These results support the hypothesis that pancreatic cancer is the cause rather than the consequence of diabetes mellitus. Key Words: Pancreatic cancer-Diabetes mellitus-MIA PaCa 2.Severall literature studies demonstrate a link between paincreatic cancer and altered glucose homeostasis (1-11). Overt diabetes mellitus and/or a reduced glucose tolerance are found in -80% of patients with pancreatic cancer (2,5,7). Several in vivo and in viiro studies attempted to identify the pathophysiological mechanism(s) responsible for the association between pancreatic cancer and diabetes mellitus. It hlas been shown that pancreatic cancerassociated diabetes does not depend on the destruction of pancreatic p cells (5,7,9) but, rather, on the Manuscript Address corrcspondence and reprint requcsts to Dott. M. Plebani.
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